Safety of switching from vitamin K antagonists to dabigatran or rivaroxaban in daily care – results from the Dresden NOAC registry
Abstract
Aim
Vitamin-K antagonists (VKA) and non-vitamin-K dependent oral anticoagulants (NOAC) have been approved for anticoagulation in venous thromboembolism (VTE) and atrial fibrillation and patients previously treated with VKA are switched to NOAC therapy. Safety data for this switching are urgently needed.
Methods
Using data from a large regional prospective registry of daily care NOAC patients, we evaluated the safety of switching anticoagulation from VKA to dabigatran or rivaroxaban. Switching procedures and cardiovascular and bleeding events occurring within 30 days after switching were centrally adjudicated.
Results
Between 1 October 2011 and 18 June 2013, 2231 patients were enrolled. Of these, 716 patients were switched from VKA to NOAC. Only 410 of the 546 evaluable patients (75.1%) had a recorded INR measurement within the 10 days preceding or following the end of VKA treatment (mean INR 2.4). As of day 30, major bleeding complications were rare (0.3%; 95% CI 0.0, 1.0) with an overall bleeding rate of 12.2% (95% CI 9.8, 14.8). Major cardiovascular events occurred in 0.8% (95% CI 0.3, 1.8). There was no significant difference in outcome event rates between the subgroups of patients with or without INR testing.
Conclusion
In daily care, only 75% of VKA patients have an INR measurement documented before NOAC are started. On average, NOAC are started within 2 to 5 days after the last intake of VKA. However, at 30 days follow-up cardiovascular events or major bleedings were rare both in patients with and without INR testing. However, switching procedures need to be further evaluated in larger cohorts of patients.
What is Already Known about this Subject
- Patients on vitamin-K antagonists (VKA) need to have their INR tested before a transition to a different anticoagulant. Different INR thresholds exist for different anticoagulants and for different indications, but existing recommendations have never been analyzed.
- Consequently, the recommendations for switching from VKA to non-vitamin-K dependent direct oral anticoagulants (NOAC or DOAC) in the summary of product characteristics (SMPCs) of the NOACs are not evidence based.
- In daily practice, considerable concerns are raised about these recommendations (initiation of NOAC at INR values <2.0 for apixaban and dabigatran in SPAF, INR <2.5 for rivaroxaban in venous thromboembolism (VTE) and INR <3.0 for rivaroxaban in stroke prevention in non-valvular atrial fibrillation (SPAF).
- In the Rocket-AF trial, major bleeding complications were highest in the subgroup of rivaroxaban patients with VKA pre-treatment compared with the subgroups of patients without VKA pre-treatment or the subgroup of pre-treated patients randomized to warfarin. This could be an indicator that the transition from VKA pre-treatment to NOAC increases bleeding risks.
What this Study Adds
- In daily practice, only 75% of all patients had a recorded INR measurement within 10 days before or after the end of VKA treatment. The baseline characteristics of patients receiving INR testing were not different from the cohort of patients without INR testing at the end of VKA treatment.
- Compared with rivaroxaban SPAF patients, patients receiving dabigatran for SPAF significantly more often had a history of stroke and were significantly more often treated with reduced NOAC dosages.
- In INR-tested patients, mean INR at the end of VKA treatment was 2.4 and, on average, physicians initiated NOAC 2.5 days after the last INR measurement.
- The rate of major cardiovascular events at day 30 after switching was 0.8%. All events occurred in SPAF patients and none in the VTE cohort. The rate of major bleeding complications at day 30 after switching was 0.3% and the overall bleeding rate was 12.2%, which was similar for SPAF and VTE patients and similar for patients with and without INR testing at the end of VKA therapy.
Introduction
Over the past 2 years, non-vitamin-K dependent oral anticoagulants (NOAC) such as dabigatran and rivaroxaban have been approved in several countries around the world as anticoagulants for stroke prevention in non-valvular atrial fibrillation (SPAF) and, in case of rivaroxaban, also for the treatment of venous thromboembolism (VTE). Large phase III trials in these indications compared dabigatran or rivaroxaban with the standard vitamin-K antagonists (VKAs) and consistently demonstrated at least equal efficacy and safety of these new drugs 1-3. Furthermore, treatment with NOAC is less challenging for patients and physicians, since coagulation monitoring and subsequent dose adjustments are not routinely required, no food restrictions apply and interactions with concomitant drugs are less relevant compared with VKA therapy 4. As a consequence, a number of long term VKA patients are switched from VKA to NOAC. Specific recommendations for the switching procedure are provided in the drug information sheets for each NOAC and each approved indication. These recommendations are derived from observations of the large phase III programmes, in which about 50 to 60% of included patients were VKA-experienced 1, 2. In general, testing of the international normalized ratio (INR) is recommended at the end of VKA therapy and the initiation of NOAC should be scheduled according to the INR test result, the indication for NOAC therapy and the respective drug used. Rivaroxaban should be started when the INR is below 3.0 in SPAF and below 2.5 in VTE patients. In contrast, dabigatran should be initiated only if the INR is below 2.0 5, 6.
However, these recommendations have never been prospectively evaluated and the translation of results from phase III trials into clinical practice is limited by the fact that selected study populations in these trials may not be representative for cohorts of unselected patients in daily care who do not need to fulfil strict inclusion and exclusion criteria and exhibit relevant comorbidities 7-9. Furthermore, in phase III trials, study procedures are performed under a strict protocol and supervision, whereas guidance and supervision of individual therapy is less strict in daily care.
Consequently, the safety of switching from VKA to NOAC therapy in daily care may differ from trial results and physicians' adherence to switching recommendations such as NOAC initiation according to INR test results should be evaluated.
The evaluation of switching from VKA to NOAC is especially important, since in the ROCKET-AF trial, where the INR threshold for rivaroxaban initiation was as high as 3.0, major bleeding complications were highest in the subgroup of VKA-experienced patients receiving rivaroxaban compared with the subgroups of patients newly anticoagulated or the subgroup of VKA-experienced patients randomized to warfarin 2. This could be an indicator that the transition from VKA to NOAC increases bleeding risks.
Using data from a large regional NOAC registry 10, we prospectively evaluated the effectiveness and safety of the switching process from VKA to NOAC in a large cohort of patients.
Methods
Patients
The Dresden NOAC registry (NCT01588119) is a large prospective registry in the administrative district of Dresden (Saxony) in Germany. In this ongoing project, a network of more than 230 physicians from private practices and hospitals enrol eligible patients, who are prospectively followed.
- planned anticoagulation with dabigatran or rivaroxaban for at least 3 months
- approved NOAC dosages for SPAF or VTE treatment
- age >18 years
- written informed consent
- availability for follow-up by telephone visits
No exclusion criteria applied.
Attending physicians document patient characteristics including demographic parameters, indication for and dosage of previous and current anticoagulation, cardiovascular, thromboembolic and bleeding risk factors, other comorbidities and concomitant medications on a paper case report form which, together with the signed informed consent form, are sent to the registry office.
Patients are followed by telephone visits performed by the central registry office at 30 days after enrolment and quarterly thereafter for at least 2 years to collect data on the effectiveness, safety and management of NOAC therapy in daily care.
Data collection
Using a standardized form, the following baseline data were collected for all patients: age, gender, height, body weight, contact data of patient and family physician, indication for anticoagulation, initiation date, type and dosage of NOAC, concomitant medication including other anticoagulants, antiplatelet drugs, non-steroidal antirheumatics (NSAIDs), HAS-BLED and CHADS-VASc score items, concomitant diseases, alcohol and smoking habits.
For VKA-experienced patients, also year of VKA initiation, reasons for switching, date and value of last INR were collected.
For all patients, the decision process for NOAC therapy (NOAC recommended and/or started by family physician, specialist, hospital) was assessed.
Analysis of switching procedure
All patients with a reported VKA pre-treatment were extracted from the database. Patients receiving intermittent heparin treatment between VKA and NOAC were excluded from analysis, since these patients underwent invasive procedures which may affect the risk for cardiovascular or bleeding events, unrelated to the later initiated NOAC therapy. Similarly, patients receiving blinded study drug anticoagulation before switching to open label NOAC were excluded from analysis.
Patients receiving off label NOAC treatment (non-approved indication or dosage) or patients receiving apixaban (because of very low numbers) were excluded from analysis of switching procedure and outcomes.
Intervals between last intake of VKA, start of NOAC and INR testing were only evaluated in patients who had a documented INR test in the 10 days preceding or following the last day of VKA intake. All other patients were only included in the demographic evaluation of the total cohort and in the evaluation of the interval between last intake of VKA and first intake of NOAC (Figure 1).
Flow chart of patient cohort and subgroups included in or excluded from subgroup analyses. SPAF = stroke prevention in atrial fibrillation; VTE = venous thromboembolism; VKA = vitamin-K antagonists; NOAC = novel oral anticoagulants; LWMH = low molecular weight heparin; INR = international normalized ratio
Of note, INR tests were performed at the practice of enrolling physicians using different point-of-care or central laboratory assays, reflecting the real-world situation.
Furthermore, the influence of adherence to the switching procedure instructions in the summary of product characteristics (SMPCs) for Germany 5, 6 on effectiveness and safety outcomes was assessed. The definition of ‘on label’ was: every transition to NOAC with INR test within last 10 days of VKA, start of NOAC within 7 days of last VKA intake and last documented INR <2.0 (dabigatran SPAF), <2.5 (rivaroxaban VTE) or <3.0 (rivaroxaban SPAF). Additionally, transition was regarded ‘on label’ in patients in whom the INR was above the recommended switching threshold (see above) but within the therapeutic INR range (2.0–3.0) and who started NOAC 3–10 days after the last VKA to allow for at least 3 days of INR decrease before NOAC initiation.
Effectiveness outcomes
- acute coronary syndrome (ACS), including unstable angina, non-ST-elevation infarction (NSTEMI) and ST-elevation infarction (STEMI)
- stroke or transient ischaemic attack (TIA), or systemic embolism
- deep vein thrombosis (DVT) or pulmonary embolism (PE).
Secondary effectiveness outcomes were the rates of all separate components of the composite endpoint, non-major cardiovascular events and death from any cause.
Safety outcomes
- documented transfusion of at least 2 units of red blood cells (RBC)
- drop in haemoglobin >2 g l−1
- surgical revision due to bleeding
- bleeding into critical sites (intracranial, intraocular, intra-articular, retroperitoneal, overt gastrointestinal bleeding)
- fatal bleeding.
Further safety outcomes were rates of any bleeding, ISTH non-major, clinically relevant bleeding (NMCR) or ISTH minor bleeding.
For all patients with suspected major cardiovascular or bleeding events, results of imaging such as ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), angiography, laboratory tests, patient charts, discharge letters, autopsy reports and death certificates were centrally adjudicated and categorized using standard scientific definitions.
Statistics
Differences in baseline variables were compared by Student's t-test (continuous variables with equal distribution) or Mann-Whitney U-test (categorical variables). Outcome event rates were compared with Fisher's exact test and 95% confidence intervals (CIs) for proportions are given according to Clopper–Pearson.
Data are shown as absolute values, percentage, standard deviation and 95% CI, or median with 25th and 75th percentile, where appropriate. A P value below 0.05 was regarded to be significant.
P values were corrected for multiple testing, as appropriate.
All statistical analyses were carried out using the IBM® SPSS® Statistics Version 19 and R (Comprehensive R Archive Network).
Ethics
The study protocol was approved by the local ethics committee at the Technische Universität Dresden, Medical Faculty (AZ EK 349092011). All patients provided written informed consent including data protection waiver before inclusion into the registry. The study is registered at ClinicalTrials.gov (NCT01588119).
Results
Cohort characteristics
Between October 1 2011 and October 22 2013, 2231 patients were enrolled into the registry. Of these, 716 patients (32.1%; Figure 1) were directly switched from VKA to either dabigatran or rivaroxaban (Figure 1) for approved indications (SPAF: n = 568, 79.3%; VTE: n = 148, 20.7%). The baseline characteristics of the total cohort as well as SPAF and VTE subgroups are shown in Table 1.
| All transitions | Transitions to dabigatran in SPAF | Transitions to rivaroxaban in SPAF | Transitions to rivaroxaban in VTE | P value dabigatran vs. rivaroxaban in SPAF | P value rivaroxaban in SPAF vs. rivaroxaban in VTE | |
|---|---|---|---|---|---|---|
| n | 716 | 126 | 442 | 148 | 126/442 | 442/148 |
| Male n (%) | 370 (51.7) | 70 (55.6) | 227 (51.4) | 73 (49.3) | 0.186 | >0.999 |
| Age (years) mean ± SD | 72.2 ± 11.6 | 75.1 ± 8.5 | 74.6 ± 8.6 | 62.9 ± 15.4 | >0.999 | <0.001 |
| BMI (kg m−2) mean ± SD | 28.7 ± 5.1 | 28.5 ± 4.2 | 28.8 ± 5.4 | 28.9 ± 5.2 | >0.999 | >0.999 |
| Diabetes n (%) | 263 (36.7) | 51 (40.5) | 183 (41.4) | 29 (19.6) | 0.852 | <0.001 |
| Hypertension n (%) | 551 (77.0) | 109 (86.5) | 359 (81.2) | 83 (56.1) | 0.169 | <0.001 |
| Chronic heart failure n (%) | 246 (34.4) | 53 (42.1) | 183 (41.4) | 10 (6.8) | 0.894 | <0.001 |
| Prior stroke or systemic embolism n (%) | 109 (15.2) | 35 (27.8) | 66 (14.9) | 8 (5.4) | 0.006 | 0.004 |
| CAD/PAOD | 139 (19.4) | 31 (24.6) | 95 (21.5) | 13 (8.8) | 0.459 | <0.001 |
| Concomitant antiplatelet therapy n (%) | 41 (5.7) | 12 (9.5) | 26 (5.9) | 3 (2.0) | 0.068 | 0.154 |
| CHA2DS2-VASc mean (IQR) | n.a. | 4 (3;5) | 4 (3;5) | n.a. | 0.808 | NA |
| HAS-BLED score >3 | 37 (5.2) | 7 (5.6) | 23 (5.2) | 7 (4.7) | 0.726 | >0.999 |
| Reduced NOAC dosage* n (%) | 252 (35.2) | 68 (53.9) | 154 (34.8) | 30 (20.3%) | <0.001 | <0.001 |
- *Reduced dosage = daily dosage <300 mg dabigatran or <20 mg rivaroxaban. Of note, data on the renal function were inconsistently documented by the enrolling physicians and were excluded from analysis. Results of statistical significance are in bold. Abbreviations are as follows: BMI, body mass index; CAD/PAOD, coronary artery disease/peripheral arterial occlusive disease; NOAC, novel oral anticoagulants; SD, standard deviation; SPAF, stroke prevention in atrial fibrillation; VKA, vitamin-K antagonists; VTE, venous thromboembolism.
Of the 716 patients switched from VKA to dabigatran or rivaroxaban, 590 patients were switched from VKA to rivaroxaban (82.4%; 442 for SPAF and 148 for VTE) and 126 were switched to dabigatran (17.6%; all for SPAF). Between the SPAF patients switched to dabigatran or rivaroxaban, no differences in age, gender or BMI were observed. Patients receiving dabigatran significantly more often had a history of stroke compared with SPAF patients receiving rivaroxaban (27.8% vs. 14.9%; P = 0.003). Furthermore, despite similar CHA2DS2-VASc scores and HAS-BLED scores, SPAF patients receiving dabigatran significantly more often were treated with lower dosages compared with SPAF patients receiving rivaroxaban (total daily dose <300 mg dabigatran in 53.9% vs. total daily dose <20 mg rivaroxaban in 34.8%; P < 0.001).
In the cohort of rivaroxaban patients, SPAF patients were older (74.6 vs. 62.9 years, P < 0.001) and more often had a history of stroke (14.9 vs. 5.4%; P = 0.004) compared with VTE patients. On the other hand, patients treated for SPAF were more often treated with a reduced dosage compared with VTE patients (total daily dose <20 mg rivaroxaban 34.8% vs. 20.3%; P < 0.001).
Reasons for switching patients from VKA to NOAC are presented in Table 2, as they were documented by the enrolling physician. Unstable INR and a history of bleeding complications were the most frequent indications to discontinue VKA, while thromboembolic complications rarely led to a change of anticoagulant therapy. In general, reported reasons to switch from VKA to NOAC were similar in SPAF and VTE patients, but SPAF patients were reported to be at risk of repeated falls significantly more often than VTE patients (12.6 vs. 5.4%; P = 0.013).
| Reasons for switching from VKA to NOAC | Transition in SPAF (n = 568) n (%) | Transition in VTE (n = 148) n (%) | P value |
|---|---|---|---|
| Unstable INR | 331 (58.3) | 87 (58.8) | 0.926 |
| Bleeding complications | 103 (18.1) | 21 (14.2) | 0.275 |
| Thromboembolic complications | 15 (2.6) | 5 (3.4) | 0.582 |
| Repeated falls | 73 (12.9) | 8 (5.4) | 0.009 |
| Others | 207 (36.4) | 57 (38.5) | 0.634 |
- Results of statistical significance are in bold. Abbreviations are as follows: INR, international normalized ratio; NOAC, novel oral anticoagulants; SPAF, stroke prevention in atrial fibrillation; VKA, vitamin-K antagonists; VTE, venous thromboembolism.
INR testing at end of VKA treatment
Of the 716 patients directly switched from VKA to dabigatran or rivaroxaban, complete data on the transition process were available for 546 patients. Of these, only 410 patients (75.3%) had a recorded INR measurement within 10 days before or after the end of VKA treatment.
The baseline characteristics of patients receiving INR testing were not different from the cohort of patients without INR testing at the end of VKA treatment (Table 3) but VTE patients more often had an INR test at the end of VKA compared with SPAF patients (85.3 vs. 71.4%; P = 0.001).
| All evaluable transitions n = 546 | Transition with INR testing n = 410 | Transition without INR testing n = 136 | INR testing vs. no INR testing | |
|---|---|---|---|---|
| Age (years) mean ± SD | 71.9 ± 11.6 | 71.5 ± 11.5 | 73.3 ± 11.8 | P = 0.119 |
| Male n (%) | 282 (51.6) | 214 (52.2) | 68 (50) | P = 0.693 |
| SPAF/VTE n (%) | 424/122 (77.7/22.3) | 305/105 (74.4/25.6) | 119/17 (87.5/12.5) | P = 0.001 |
| Interval (days) between last VKA and first NOAC intake Median (IQR) | 2 (3) | 2 (3) | 2 (3) | P = 0.455 |
| Transition from VKA to NOAC by GP/specialist |
260/286 52.4/47.6 |
205/205 50/50 |
81/55 59.6/40.4 |
P = 0.060 |
| Prior stroke or systemic embolism n (%) | 73 (13.4) | 54 (13.2) | 19 (14.0) | P = 0.884 |
| Concomitant antiplatelet therapy n (%) | 27 (4.9) | 20(4.9) | 7 (5.1) | P > 0.999 |
| HAS-BLED score >3 | 26 (4.8) | 19 (4.6) | 7 (5.1) | P = 0.817 |
- Results of statistical significance are in bold. Abbreviations are as follows: GP, general practitioner; INR, international normalized ratio; IQR, interquartile range; NOAC, novel oral anticoagulants; SD, standard deviation; SPAF, stroke prevention in atrial fibrillation; VKA, vitamin-K antagonists; VTE, venous thromboembolism.
In the 410 patients with INR testing at the end of VKA therapy (mean INR 2.2 ± 1.5), the median interval between last intake of VKA and INR testing was 0 days for all patients (IQR 3). This was similar for SPAF patients receiving dabigatran and rivaroxaban, respectively (Table 4).
| All evaluable patients n = 546 | Evaluable SPAF transitions to dabigatran n = 88 | Evaluable SPAF transitions to rivaroxaban n = 336 | Evaluable VTE transitions to rivaroxaban n = 122 | P value dabigatran vs. rivaroxaban in SPAF | P value rivaroxaban in SPAF vs. rivaroxaban in VTE | |
|---|---|---|---|---|---|---|
| INR tested, n (%) | 410 (75.3) | 63 (72.7) | 241 (71.7) | 104 (85.3) | >0.999 | 0.002 |
| Interval (days) between last VKA intake and INR testing median (IQR) | 0 (3) | 0 (4) | 0 (3.5) | -1 (1.8) | >0.999 | 0.004 |
|
Last INR value mean ± SD |
2.4 ± 1.5 | 2.6 ± 1.6 | 2.4 ± 1.2 | 2.4 ± 1.9 | 0.626 | >0.999 |
| Interval (days) between last INR and first NOAC intake median (IQR) | 2.5 (6) | 4 (8.8) | 3 (6) | 2 (4) | 0.882 | 0.002 |
| Interval (days) between last VKA and first NOAC intake median (IQR) | 2 (3) | 2 (8) | 2 (3) | 2 (3) | 0.440 | >0.999 |
- Results of statistical significance are in bold. Abbreviations are as follows: INR, international normalized ratio; IQR, interquartile range; NOAC, novel oral anticoagulants; SPAF, stroke prevention in atrial fibrillation; VKA, vitamin-K antagonists; VTE, venous thromboembolism.
In contrast, the median interval between last intake of VKA and INR testing was −1 day (IQR 1.8) for VTE patients switched to rivaroxaban, which was significantly different from the respective SPAF cohort (P = 0.004).
Furthermore, the median interval between INR testing and first intake of NOAC was 2.5 days for all patients (IQR 6) and not significantly different between 4 days for SPAF patients receiving dabigatran (4 days; IQR 8.8) or rivaroxaban (3 days; IQR 6; P = 0.882). In contrast, the median interval between INR testing and first intake of NOAC was significantly shorter for VTE patients switched to rivaroxaban (median 2 days; IQR 4) compared with the respective SPAF cohort (P = 0.002).
Finally, the median interval between last intake of VKA and first intake of NOAC was 2 days for all patients (IQR 3) and not significantly different between the subgroups (SPAF patients receiving dabigatran 2 days; IQR 8; SPAF patients receiving rivaroxaban 2 days; IQR 3; VTE patients receiving rivaroxaban 2 days; IQR 3).
Effectiveness and safety endpoints at day 30 after switching from VKA to NOAC
Thirty days after switching, 701 (97.9%) of the patients were still taking the initial NOAC medication. The remaining 15 patients discontinued NOAC due to bleeding (three non-major clinically relevant, one minor and one major bleeding), dyspepsia (four cases), fatigue (two cases), vertigo (one case) and in two cases due to patient concerns (following news reports of side effects) or reimbursement concerns of the family physician. Patients were transitioned back to VKA in eight cases, continued on aspirin (three cases) or low molecular weight heparin (one case), changed from dabigatran to rivaroxaban (two cases) or completely stopped anticoagulation (one case). All 15 patients remained in the study, underwent further follow-up visits and were part of the outcome event assessment.
Between the start of NOAC therapy and day 30, six patients experienced major cardiovascular events (0.8%; 95% CI 0.3, 1.8), which consisted of three ACSs, two TIAs and one systemic embolism leading to acute limb ischaemia of the lower extremity. None of these events was fatal. All events occurred in SPAF patients (one patient with a CHADS2 score of 1, one patient with a CHADS2 score of 3, two patients with a CHADS2 score of 4 and two with a CHADS2 score of 5, respectively) and none in the VTE cohort (Table 5).
| Outcome at day 30 after start of NOAC | All transitions n = 716 n (%, 95% CI) | SPAF transitions n = 568 n (%, 95% CI) | VTE transitions n = 148 n (%, 95% CI) | P value SPAF vs. VTE |
|---|---|---|---|---|
| Major CV events | 6 (0.8; 0.3, 1.8) | 6 (1.1; 0.4, 2.3) | 0 (0.0; 0.0, 2.5) | 0.354 |
| Any bleeding | 87 (12.2; 9.8, 14.8) | 66 (11.6; 9.1, 14.5) | 21 (14.2; 9.0, 20.9) | 0.398 |
| Minor bleeding | 48 (6.7; 5.0, 8.8) | 35 (6.2; 4.3, 8.5) | 13 (8.8; 4.8, 14.6) | 0.269 |
| NMCR bleeding | 27 (3.8; 2.5, 5.4) | 21 (3.7; 2.3, 5.6) | 6 (4.1; 1.5, 8.6) | 0.810 |
| Major bleeding | 2 (0.3; 0.0, 1.0) | 1 (0.2; 0.0, 1.0) | 1 (0.7; 0.0, 3.7) | 0.371 |
| Death | 4 (0.5; 0.1, 1.5) | 3 (0.5; 0.1, 1.5) | 1 (0.7; 0.0, 3.7) | >0.999 |
- Abbreviations are as follows: CI, confidence interval; CV, cardiovascular; NMCR, non-major clinically relevant bleeding; NOAC, novel oral anticoagulants; SPAF, stroke prevention in atrial fibrillation; VKA, vitamin-K antagonists; VTE, venous thromboembolism.
Of note, three of the six cardiovascular events occurred in patients who had an INR testing at the end of VKA therapy (INR values of 1.0, 1.6 and 2.2, respectively) and the remaining three events occurred in non-evaluable patients (neither last day of VKA nor INR testing documented), while no event occurred in evaluable patients without INR testing (Table 6).
| All patients n = 716 n (%; 95% CI) | Transition not evaluable n = 170 n (%, 95% CI) | Transition with INR testing n = 410 n (%, 95% CI) | Transition without INR testing n = 136 n (%, 95% CI) | P value INR testing vs. no INR testing | |
|---|---|---|---|---|---|
| Major CV events | 6 (0.8; 0.3, 1.8) | 3 (1.8; 0.4, 5.1) | 3 (0.7; 0.2, 2.1) | 0 (0.0; 0.0, 2.7) | >0.999 |
| Any bleeding | 87 (12.2; 9.8, 14.8) | 15 (8.8; 5.0, 14.1) | 55 (13.4; 10.3, 17.1) | 17 (12.5; 7.5, 19.3) | 0.884 |
| Minor bleeding | 48 (6.7; 5.0, 8.8) | 11 (6.5; 3.3, 11.3) | 27 (6.6; 4.4, 9.4) | 10 (7.4; 3.6, 13.1) | 0.844 |
| NMCR bleeding | 27 (3.8; 2.5, 5.4) | 3 (1.8; 0.4, 5.1) | 22 (5.4; 3.4, 8.0) | 2 (1.5; 0.2, 5.2) | 0.056 |
| Major bleeding | 2 (0.3; 0.0, 1.0) | 0 (0.0; 0.0, 2.1) | 2 (0.5; 0.1, 1.8) | 0 (0.0; 0.0, 2.7) | >0.999 |
| Death | 4 (0.5; 0.1, 1.5) | 2 (1.2; 0.1, 4.2) | 1 (0.2; 0.0, 1.4) | 1 (0.7; 0.0, 4.0) | 0.436 |
- Abbreviations are as follows: CI, confidence interval; CV, cardiovascular; INR, international normalized ratio; NMCR, non-major clinically relevant bleeding.
Until day 30, two patients experienced major bleeding complications (0.3%; 95% CI 0.0, 1.0; one SPAF and one VTE patient). In total, 87 patients experienced bleeding complications (12.2%; 95% CI 9.8, 14.8) without significant differences between SPAF or VTE patients. Overall, rates of bleeding complications were comparable between the cohort with and without INR testing at the end of VKA therapy (Table 6).
Patients who had been on VKA for more than 3 months before transition to NOAC had significantly lower rates of major cardiovascular complications (0.4%, 95% CI 0.0, 1.5) compared with patients who had started VKA within 3 months before transition to NOAC (4.3%, 95% CI 0.5, 14.5; P = 0.041). Similarly, these patients also had numerically lower rates of major bleeding complications (0.0%, 95% CI 0.0, 7.5 vs. 0.4%, 95% CI 0.0, 1.5), which failed to reach statistical significance (P = 0.999). More specifically, both major bleedings observed during follow-up occurred in patients who had started VKA within 3 months before transition.
Furthermore, the influence of adherence to the switching procedure instructions in the SMPCs for Germany on effectiveness and safety outcomes was assessed (Table 7). Of the 546 evaluable patients, 299 were switched according to label (54.7%). Regarding the event rates of major cardiovascular or bleeding complications, no significant differences were found between the cohort switched according to label and the ‘off label’ cohort.
| All evaluable patients n = 546 n (%; 95% CI) | Switching according to label n = 299 n (%, 95% CI) | Switching not according to label n = 247 n (%, 95% CI) | P value | |
|---|---|---|---|---|
| Major CV events | n = 4 (0.7%; 0.2, 1.9) | n = 4 (1.3%; 0.4, 3.4) | n = 0 (0.0%; 0.0, 1.5) | 0.130 |
| Any bleeding | n = 72 (13.2%; 10.5, 16.3) | n = 40 (13.4%; 9.7, 17.8) | n = 32 (13.0%; 9.0, 17.8) | 0.900 |
| Minor bleeding | n = 37 (6.8%; 4.8, 9.2) | n = 18 (6.0%; 3.6, 9.3) | n = 19 (7.7%; 7.7, 11.8) | 0.495 |
| NMCR bleeding | n = 24 (4.4%; 2.8, 6.5) | n = 15 (5.0%; 2.8, 8.1) | n = 9 (3.6%; 1.7, 6.8) | 0.531 |
| Major bleeding | n = 2 (0.4%; 0.0, 1.3) | n = 2 (0.7%; 0.0, 2.4) | n = 0 (0.0%; 0.0, 1.5) | 0.504 |
| Death | n = 2 (0.4%; 0.0, 1.3) | n = 1 (0.3%; 0.0, 1.8) | n = 1 (0.4%; 0.0, 2.2) | >0.999 |
- NMCR, non-major clinially relevant bleeding.
Four patients (0.5%, 95% CI 0.1, 1.5) died by day 30. These included three SPAF patients (one fatal intracranial bleeding, also included in major bleeding analysis; one sudden cardiac death, also included in major cardiovascular event analysis, one terminal chronic heart failure) and one VTE patient who died of septic multi-organ failure after elective cardiac surgery.
Due to the low rate of cardiovascular and major bleeding events or deaths until day 30 it was not possible to perform a multivariate analysis to evaluate potential risk factors for unfavourable outcomes.
Discussion
Our data are the first that systematically describe and analyze the management and outcome of patients who are switched from VKA to NOAC in daily care. In a large cohort of over 700 patients we found that only 75% of patients with VKA pre-treatment underwent INR testing before NOAC therapy was initiated. This is in contrast to the label of NOACs, which requires INR testing at the end of VKA therapy for all patients and recommends initiation of NOAC at specific INR values.
Another finding in our analyses was that most patients started the intake of the first dose of NOAC 2 days after the last intake of VKA, which was not different for patients with or without INR testing or in the subgroups of SPAF and VTE patients.
Furthermore, we found that in patients undergoing INR testing the mean INR value was 2.4. Despite this, NOAC therapy was not immediately started but only after 2 to 5 days, which was not different for SPAF patients switched to dabigatran or rivaroxaban. This observation is especially of interest, as both drugs have different label recommendations with regard to INR thresholds (initiation of rivaroxaban at INR values below 3.0 compared with initiation of dabigatran at INR values below 2.0).
Interestingly, the indication for anticoagulant therapy also seemed to influence the switching procedure. Despite similar mean INR values at the end of VKA therapy, rivaroxaban was started earlier in VTE patients than in SPAF patients, which was statistically significant. This finding, together with the fact that INR testing at the end of VKA therapy was performed more often in VTE patients than in SPAF patients could indicate that attending physicians are more concerned about thromboembolic complications in chronic VTE patients than in SPAF patients. On the other hand, initiation of rivaroxaban early after the last intake of VKA in VTE patients may also indicate that physicians are less concerned about bleeding risk in VTE patients, who were significantly younger than SPAF patients.
Our data also show that switching from VKA to NOAC therapy is associated with a risk of major bleeding complications as low as 0.3% at 30 days. On the other hand, the total bleeding rate at day 30 was 12% despite the fact that 75% of the patients underwent INR testing and that NOAC start was delayed by 1 to 2 days despite a mean INR in the lower therapeutic range. As a consequence, patients should be specifically informed about this bleeding risk and should be instructed to seek immediate medical attention in cases of bleeding signs.
We agree that a 12% overall bleeding event rate in a 30 day observational period is rather high. On the other hand, according to our protocol the follow-up contact occurred within 30 days after transition from VKA to NOAC. Therefore, a significant proportion of the follow-up period consisted of days of overlapping anticoagulation, where VKA still had residual action and NOAC already were given in therapeutic dosages. Therefore, one should not use the reported 30 days event rate to extrapolate annual incidences.
We believe that the comparatively high number of bleeding events observed mainly relates to a close surveillance of all patients (lost to follow-up rate was 0%), who were actively questioned about bleeding events during the quarterly phone visits. It is important to note that most events were minor bleeds and that rates of major bleeding were low with 0.3% in the total cohort and 0.4% in the cohort evaluable for switching procedure.
Major cardiovascular events occurred in 0.8% of patients within 30 days after the start of NOAC therapy despite the fact that the median interval between last VKA and first NOAC intake was only 2 days for all patients. On the other hand, most of the major cardiovascular events occurred late after switching (only the peripheral systemic embolism occurred in the first week of NOAC treatment, whereas the remaining five events, three ACS and two TIA, occurred between days 18 and 30), which might relate to lack of efficacy of NOAC or to patients incompliance rather than the switching procedure itself.
Of note, all cardiovascular events occurred in SPAF patients and five out of six in patients with a CHADS2 score ≥3), which clearly indicates the higher risk of these patients.
Interestingly, rates of bleeding and cardiovascular complications were not significantly different between the cohorts with and without INR testing. Although INR testing at the end of VKA therapy can identify sub- or supra-therapeutic INR values, it does not seem to affect the rates of bleeding or cardiovascular complications during the transition process in the majority of patients. As a consequence, one could argue that INR testing at the end of VKA therapy is not necessary, especially since the recommended thresholds to start NOAC below certain INR levels have never been prospectively evaluated. While our data seem to support such considerations, we need to point out that our evaluation cohort consisted of only 716 patients with low complication rates and that our analyses might have been underpowered to detect statistically significant differences between patients with and without INR testing. Similarly, we were not able to detect significant differences for unfavourable outcomes between cohorts switched according to the recommendations in the SMPCs and patients switched ‘off label’. Again, we need to point out that our study might have been underpowered to detect such differences.
On the other hand, our data indicated that patients who had a longer period of VKA pre-treatment (>3 months) had significantly lower rates of major cardiovascular events and at least numerically lower rates of major bleeding complications. This finding is in line with observations from VKA studies which demonstrated higher complication rates within the first three to 6 months of oral anticoagulation 12, 13.
It is difficult to compare our findings in the context of available data, since similar analyses are not available. However, in the ROCKET-AF trial evaluating rivaroxaban in SPAF, an increase of the primary efficacy outcome of stroke or systemic embolism was seen within 30 days after the end of study treatment, when patients were switched from blinded study drug to open label VKA 2, which also indicates that switching of anticoagulation is associated with increased short term risk of cardiovascular events.
Limitations
There are several limitations to our study. First of all, the design of our registry introduces the possibility of a selection bias, since local physicians within the network are not instructed which of their patients should receive NOAC or VKA therapy. Since it can be assumed that physicians are more likely to switch patients to NOAC therapy after VKA-related complications, our cohort might reflect a selection of high risk patients. On the other hand, our results indicate that switching from VKA to NOAC is safe in this cohort.
Due to the low rate of cardiovascular and major bleeding events until day 30 it was not possible to perform a multivariate analysis to evaluate potential risk factors for unfavourable outcomes. While the low event rate in our cohort of patients of high cardiovascular risk is reassuring that the switching procedure from VKA to NOAC is safe, data from larger patient cohorts should be analyzed for such risk factors in future.
Finally, the evaluation of potential outcome measures relied mostly on patient contact and patient-derived information. While all suspected outcome events were centrally adjudicated based on collected documents from family doctors, specialists in private practices and hospitals, it is possible that some events remained unreported. However, the high rate of minor events reported in our registry (rate for any bleeding 12%) and the low rate of lost-to-follow-up (below 1%) are clear indicators that the risk of unreported outcome events in our registry is low. On the other hand, the process of central adjudication is used to ensure correct categorization of outcome events but also to reduce the risk of over-reporting.
The size of our cohort and the prospective evaluation of switching procedures of more than 700 unselected daily care patients is a significant strength of our study. Furthermore, the use of clinically relevant endpoints (objectively confirmed major cardiovascular events, major bleeding complications, death from all causes) contributes to the strength and clinical impact of our data.
In conclusion, our study is the first to evaluate the effectiveness and safety of switching from VKA to NOAC in an unselected cohort of patients from daily care. Our data indicate that in about 25% of patients the recommendation to measure INR at the end of VKA is not being followed in daily care.
Overall, our data indicate that switching from VKA to NOAC in daily care has comparatively high bleeding rates but low rates for major bleeding or major cardiovascular events in the first 30 days. Further data are necessary to identify patients at risk for immediate thromboembolic and bleeding episodes during the switching procedure and to develop preventive measures to avoid these potentially devastating complications. Furthermore, we believe that our data indicate the need to study the so far not evaluated manufacturers' recommendations for switching from VKA to NOAC. This should be done prospectively in a larger cohort of daily care patients.
Competing Interests
All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare The NOAC registry is supported by the Gesellschaft für Technologie- und Wissenstransfer der TU-Dresden (GWT-TUD GmbH), Germany (sponsor), by research funds of the University Hospital Carl Gustav Carus, Dresden, Department of Vascular Medicine and by grants from Bayer Healthcare, Boehringer Ingelheim and Pfizer. All authors declare that these companies and institutions had no influence on the study design, conduct of the study, data collection, statistical analysis or preparation of the manuscript.
JBW has received honoraria and research support from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer. CK and SW have received honoraria from Bayer Healthcare. NW has received honoraria and research support from Bayer Healthcare, Boehringer Ingelheim and Pfizer. None of the authors declared a conflict of interest with regard to the NOAC registry or this manuscript.
Contributors
Maria Eulitz, Thomas Schreier, Antje Reitter, Katharina Daschkow, Bianca Sehr, Monique Leistner, Ines Beyer-Westendorf contributed to the NOAC registry by performing patient visits, entering data and collecting all necessary documents for event adjudication.
